The purpose of this present work is to determine if diabetic (and galactosemic) animals have altered metabolism of lipid (and protein) in their peripheral nerves as compared with normal animals. Efforts will be focused on quantitative changes in phosphoinositide metabolism in streptozotocin-induced diabetic rats, db/db genetically diabetic mice and galactosemic rats/mice. Both quantitative EM autoradiographic and biochemical approaches will be taken and the status of the neuropathy will be determined by measurements of nerve conduction velocity and nerve sugar alcohol and myo-inositol levels. The autoradiographic studies (both in vivo and with incubated nerves) will be designed to quantitate the uptake and incorporation of tritiated myo-inositol into phospholipid, and the subsequent redistribution of the axonal pool of newly formed lipid to axolemma, and the transfer of Schwann cell formed lipid to myelin and the subsequent movement through the sheath. These studies will assess this metabolism in proximal and distal portions of nerve separately, and each analysis will be performed to generate separate data for fibers of different caliber. Initial studies with radioactive myoinositol as precursor will be followed up by studies with 33P-orthophosphate, and tritiated choline and fucose precursors. Biochemical studies will be undertaken to determine the kinetics of uptake of labeled myoinositol into isolated peripheral nerve. Comparisons will be made between proximal and distal nerve of normal control animals, and then nerves from diabetic animals will be used to look for differences. Studies will be undertaken on the distribution of various enzymes (those involved in inositide metabolism and membrane markers) along nerve and the possible axonal transport of these enzymes in diabetic and galactosemic models. The condition of the neurons and the axonal transport system will be further characterized by following the movement of labeled proteins and lipids along the nerve following injections of precursors into the lumbar spinal cord. Once metabolic differences are revealed, various treatments (e.g., insulin) will be used to try and reverse the metabolic impairments.